Vitamin D Deficiency in HIV Infection: Not Only a Bone Disorder
Table 1
Prevalence of hypovitaminosis D in HIV-infected subjects reported by nation.
Authors (year), journal
Nation
Patients
Results
Comments
Dao et al. (2011) [23], Clinical Infectious Diseases
US
672 HIV-positive patients versus US general population.
70.3% patients had 25(OH)D levels below 30 ng/mL versus 79.1% of HIV-negative US adults.
Vitamin D deficiency was not different between the two groups and no relationship could be found with duration since HIV diagnosis and vitamin D deficiency.
Adeyemi, Agniel et al. (2011), Journal of Acquired Immune Deficiency Syndromes
US
1268 HIV-positive versus 510 HIV-negative women.
60% patients had 25(OH)D levels below 20 ng/mL versus 72% of controls.
Vitamin D deficiency was found in total 63% of women with the highest rates in African American women. No other predictive factors of hypovitaminosis were found in multivariate analysis.
Eckard, Judd et al. (2012), Antiviral Therapy
US
200 HIV-infected and 50 HIV-uninfected youth Americans.
77% of HIV-positive and 74% of controls had 25(OH)D <20 ng/mL.
No difference in 25(OH)D was proved between groups. However, with a 77% and 96% prevalence of vitamin D deficiency and insufficiency, nearly all HIV-infected youth suffered from these conditions.
Poowuttikul, Thomas et al. (2014), Journal of the International Association of Providers of AIDS Care
US
160 HIV-infected youth.
5% had normal 25(OH)D levels; 23.1% had 25(OH)D levels between 21 and 35 ng/mL; 71.9% had 25(OH)D level ≤20 ng/mL.
Severe vitamin D deficiency (25(OH)D ≤10 ng/mL) was related to lower CD4 counts and CD4% but not to HIV plasma RNA. CD4 counts/CD4% did not increase under vitamin D supplementation.
Crutchley, Gathe et al. (2012), AIDS Research and Human Retroviruses
US
200 HIV-infected patients.
64% had 25(OH)D <20 ng/mL and 20.5% had 25(OH)D <10 ng/mL.
Multivariate analysis showed a significant correlation between low 25(OH)D levels, African-American race, and low daily vitamin D supplemental intake.
Stein, Yin et al. (2011), Osteoporosis International
US
89 HIV-positive and 95 HIV-negative postmenopausal women (33% Afro-Americans and 67% Hispanic).
74% of HIV-positive versus 78% of HIV-negative women had 25(OH)D <30 ng/mL.
25(OH)D was significantly lower in Afro-American subjects and higher in subjects who used both calcium and multivitamins. 25(OH)D level was directly associated with current CD4 count (). No association was observed between 1,25(OH)(2)D and CD4 count or between serum 25(OH)D, 1,25(OH)(2)D, and type of cART.
Kwan, Eckhardt et al. (2012), AIDS Research and Human Retroviruses
In this population, hyperparathyroidism prevalence was 30% in patients with vitamin D deficiency, 23% in those with insufficiency, and 12% in those with sufficient vitamin D levels.
French, Adeyemi et al. (2011), J Womens Health (Larchmt)
US
602 nonpregnant (480 HIV-infected and 122 uninfected) subjects.
Only race was significantly associated with vitamin D deficiency, with no differences in HIV status.
Yin, Lu et al. (2010), Journal of Acquired Immune Deficiency Syndromes
US
100 HIV-positive and 68 HIV-negative premenopausal women.
91% of HIV-positive and 91% of HIV-negative had 25(OH)D levels <32 ng/mL; 69% of HIV-positive and 60% of HIV-negative had 25(OH)D levels <20 ng/mL; 30% of HIV-positive and 24% of HIV−negative had 25(OH)D <10 ng/mL.
In premenopausal HIV+ women, bone mineral density was lower than comparable HIV-women. Vitamin D level was not associated with differences in HIV status.
Rodriguez, Daniels et al. (2009), AIDS Research and Human Retroviruses
US
57 HIV-positive patients.
36.8% patients had 25(OH)D <20 ng/mL. 10.5% patients had 25(OH)D <10 ng/mL.
Lower vitamin D intake was significantly associated with severe 25(OH)D deficiency. Lactose intolerance tended to be associated with severe 25 (OH)D deficiency.
Wasserman and Rubin (2010) [17], AIDS Patient Care STDS
US
19 HIV-positive patients under NNRTI versus 37 HIV-positive patients under PI.
73.7 NNRTI recipients had 25(OH)D <50 nmol/L. 29.7 (11/37) PI recipients had 25(OH)D <50 nmol/L.
Vitamin D deficiency was not correlated to stable viral suppression. HAART receipt and tobacco use were associated with lower vitamin D levels and greater risk of deficiency and severe deficiency, respectively.
23.7% had 25(OH)D <10 ng/mL. 65.3% had 25(OH)D between 10 and 30 ng/mL. 11% had 25(OH)D >30 ng/mL.
As in the general population, season (winter), age (older), and race (black) affected 25(OH)D levels (reduction). Hypovitaminosis D was independently associated with a higher risk of HIV disease progression, AIDS events, and all-cause mortality.
Allavena, Delpierre et al. (2012), Journal of Antimicrobial Chemotherapy
France
2994 HIV-positive patients.
55.6% had 25(OH)D <30 ng/mL. 31.1% had 25(OH)D <10 ng/mL.
No relationship was found in duration since HIV diagnosis and vitamin D deficiency.
Meyzer, Frange et al. (2013), Pediatr Infect Dis J
France
113 HIV-infected children versus 54 healthy controls.
70% versus 45% had 25(OH)D <30 ng/mL. 25% versus 55% had 25(OH)D <10 ng/mL.
Dark phototype was the only independent risk factor for vitamin D deficiency in HIV-infected children.
89.2% had 25(OH)D <30 ng/mL. 32.4% had 25(OH)D <10 ng/mL.
The authors also found a positive association between AIDS diagnosis and vitamin D deficiency; in particular, it was associated with cART modalities and duration.
Van Den Bout-Van Den Beukel et al. (2008) [52], AIDS Research and Human Retroviruses
Netherlands
252 HIV-positive patients.
28.96% had 25(OH)D <35 nmol/L from April to September and <25 nmol/L from October to March.
Female sex, younger age, dark skin, and NNRTI treatment were significant risk factors in univariate analysis, although in multivariate analyses skin pigmentation remained the only independent risk factor.
Bang, Shakar et al. (2010), Scand J Infect Dis
Denmark
115 HIV-positive patients.
20.0% had 25(OH)D <25 nmol/L. 4.0% had 25(OH)D <12.5 nmol/L.
Vitamin D level was not associated with age, with HIV infection, highly active antiretroviral therapy (HAART) or CD4 count.
Welz, Childs et al. (2010) AIDS
UK
1077 HIV-positive patients
91% 25(OH)D <30 ng/mL 33% 25(OH)D <10 ng/mL
Black ethnicity, sampling in winter, CD4 cell count lower than 200 cells/microl, and exposure to combination antiretroviral therapy were associated with severe vitamin D deficiency.
Gedela et al. (2014) [18], International Journal of STD & AIDS
UK
253 HAART-naive subjects.
58.5% had 25(OH)D <30 ng/mL. 12.6% had 25(OH)D <10 ng/mL.
25(OH)D deficiency was common among antiretroviral treatment-naive patients, with those of nonwhite ethnicity at highest risk; no association was found with CD4 count, HIV viral load, and HIV clinical staging.
Mueller, Fux et al. (2010), AIDS
Swiss
211 HAART-naive subjects.
42% had 25(OH)D <30 ng/mL in spring. 14% had 25(OH)D <30 ng/mL in fall.
Vitamin D status significantly changed in HIV-positive patients according to seasons, intravenous drugs use, and longer HIV diagnosis but remained unchanged regardless of combined cART exposure.
Haug, Aukrust et al. (1998), Journal of Clinical Endocrinology and Metabolism
Norway
54 HIV-positive patients.
54% had 1,25(OH)2D <95 pmol/L and 62% of them had undetectable levels.
HIV-patients had low 1,25(OH)2D levels, whereas they had normal serum levels of 25(OH)D and vitamin D-binding protein. Moreover, they had modestly depressed serum calcium and PTH levels. No correlations were found between these parameters and serum levels of 1,25(OH)2D. Patients with undetectable 1,25(OH)2D were characterized by advanced clinical HIV infection, low CD4+ lymphocyte counts, and high serum levels of TNF-alpha. Inadequate 1alpha-hydroxylation of 25(OH)D could be the cause of 1,25(OH)2D deficiency, possibly induced by an inhibitory effect of TNF-alpha.
Vescini, Cozzi-Lepri et al. (2011), Journal of Acquired Immune Deficiency Syndromes
Italy
810 HIV-positive patients.
47% had 25(OH)D <30 nmol/L. 3% had 25(OH)D <10 nmol/L.
Authors highlighted a correlation between 25(OH)D insufficiency and risk of cardiovascular events, diabetes mellitus, and renal disease over a median 6.5-year follow-up. 25(OH)D levels below 30 nmol/L seemed to predict faster HIV progression.
Pinzone, Di Rosa et al. (2013), Eur. Rev. Med. Pharmacol. Sci.
Italy
91 HIV-positive patients.
57% patients had 25(OH)D <30 ng/mL. 31% patients had 25(OH)D <10 ng/mL.
Vitamin D deficiency was common in HIV-infected patients. Chronic inflammation, including residual viral replication, may contribute to 25(OH)D reduction modulating vitamin D metabolism and catabolism.
Cervero, Agud et al. (2012), AIDS Research and Human Retroviruses
Spain
352 HIV-positive patients.
71.6% had 25(OH)D <30 ng/mL. 44.0% had 25(OH)D <20 ng/mL.
Higher body mass index, black race, lower seasonal sunlight exposure, men who have sex with men and heterosexual transmission categories, efavirenz exposure, and lack of HIV viral suppression were independently associated with 25(OH)D deficiency/insufficiency.
Lerma, Molas et al. (2012), ISRN AIDS
Spain
566 HIV-positive patients.
71.2% had 25(OH)D <30 ng/mL; 39.6% had 25(OH)D <20 ng/mL.
Nonwhite race and psychiatric comorbidity were predictors of vitamin D deficiency.
Teichmann et al. (2000) [56], Journal of Infection
Germany
54 HIV-positive females prior to HAART versus 50 healthy women.
1,25(OH)2D levels in HIV-positive women, 19.4 ± 7.2; 1,25(OH)2D levels in healthy women, 47.3 ± 9.1; 25(OH)D levels in HIV-positive women, 37.3 ± 7.9; 25(OH)D levels in healthy women, 61.5 ± 8.4.
Lumbar osteoporosis was found in 7 patients (14%) versus 0 controls; lumbar osteopenia was diagnosed in 31 (62%) patients and 2 (4%) controls. There was significant correlation between the CD4 counts and 1,25(OH)2D levels. Neither the CD4 counts nor the duration of disease correlated with BMD
Etminani-Esfahani, Khalili et al. (2012), Current HIV Research
Iran
98 HIV-positive patients.
86.7% had 25(OH)D <35 nmol/L.
Female sex, unemployment, and human hepatitis C coinfection were related to the severe serum vitamin D deficiency.
Bajaj, Misra et al. (2012), Indian Journal of Endocrinology and Metabolism
India
45 HIV-positive patients. 45 healthy controls.
93.33% patients had 25(OH)D <30 ng/mL. 73.33% patients had 25(OH)D <30 ng/mL.
51.11% patients had dyslipidemia compared to 15.55% of controls. A positive association was proved between CD4 levels and 25(OH)D. No significant difference was seen in carotid intima-media thickness in cases and controls.
Conrado, Miranda-Filho Dde et al. (2011), Journal of the International Association of Providers of AIDS Care (Chic)
Brazil
214 HIV-positive female patients on cART.
40.65% patients had 25(OH)D <30 ng/mL.
Multivariate analysis proved that hypercholesterolemia and cART ≥3 years were positively associated with 25(OH)D deficiency, whereas there was an inverse statistically significant correlation with total cholesterol.
Wiboonchutikul, Sungkanuparph et al. (2012), Journal of the International Association of Providers of AIDS Care (Chic)
Thailand
178 HIV-positive patients.
44.9% had 25(OH)D <30 ng/mL and 26.8% had 25(OH)D <20 ng/mL.
Efavirenz intake was significantly associated with low vitamin D status. The mean 25(OH)D levels in patients receiving and not receiving EFV were, respectively, 22.9 and 28.6 ng/mL.
Conesa-Botella, Goovaerts et al. (2012), International Journal of Tuberculosis and Lung Disease
41% patients of G1 had 25(OH)D <75 nmol/L. 35% patients of G2 had 25(OH)D <75 nmol/L. 37% patients of G3 had 25(OH)D <75 nmol/L. 65% patients of G4 had 25(OH)D <75 nmol/L.
The authors reported that the prevalence of optimal vitamin D status was relatively high in HIV-infected patients with and without TB living in Uganda near the equator.
Mastala, Nyangulu et al. (2013), PLoS One
Malawi
69 HIV-positive of 157 TB negative patients.
23.1% of HIV-positive patients had 25(OH)D <50 nmol/L.
25(OH)D deficiency seemed more common in TB patients than non-TB patients. No significant correlation was found with HIV-status.
Rwebembera, Sudfeld et al. (2013), J Trop Pediatr
Tanzania
191 HIV-exposed uninfected infants.
48.7% had 25(OH)D <30 ng/mL. 34.6% had 25(OH)D <20 ng/mL.
25(OH)D deficiency was associated with sampling during the rainy season and infant wasting, whereas infant breastfeeding, maternal CD4 T-cell count, maternal wasting status, and maternal receipt of cART were not associated.
Havers et al. (2014) [24], The Journal of Infectious Diseases
US and 8 resource-limited countries
411 patients from PEARLS trial.
49% had 25(OH)D <32 ng/mL.
25(OH)D deficiency ranged from 27% in Brazil to 78% in Thailand. It was associated with high body mass index, winter/spring season, country-race group, and lower viral load. In addition, baseline low 25(OH)D was associated with increased risk of HIV progression, death, and virologic failure after cART.
1,25(OH)(2)D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; AIDS: acquired immune deficiency syndrome; cART: combined antiretroviral therapy; BMD: bone mass density; HAART: highly active antiretroviral therapy; NNRTI: nonnucleoside reverse-transcriptase inhibitor; PI: protease inhibitor; PTH: parathyroid hormone; US: United States; TB: tuberculosis; TNF-alpha: tumor necrosis factor-alpha; UK: United Kingdom.
